Currently the identity of precursors of the mesenchymal cells involved in wound healing and fibrosis are under debate. We propose a novel paradigm in which these cells descend from a unique subpopulation of repair progenitor cells that coexist normally with the cells of epithelial tissues. We have shown the presence of these repair cells in the lens and cornea. In the lens these repair progenitor cells rapidly respond to injury by expanding their population size through a mechanism independent of DNA replication, but likely related to their unusual characteristic of polyploidy. The signals that mediate the expansion of the progenitor cells, their reprogramming to a repair phenotype and the rapid targeting of the repair cells to the wound edge are unknown. While the repair cells function at the site of injury as regulators of the healing process, they also have the potential to transdifferentiate to a myofibroblast phenotype, the cell type linked to fibrosis. This proposal examines this novel wound healing paradigm in both lens and cornea injury models with the following questions: 1) Are the repair progenitor cells novel descendents of a hematopoietic lineage?;2) What is the mechanism by which repair cell progenitors rapidly expand in response to injury of their host epithelium?;3) How are mesenchymal progenitor cells signaled to migrate to the wound edge?;4) What is the fate of the mesenchymal cells after they complete their job of regulating wound repair?;and 5) What are the conditions that induce the repair cells to acquire the mature myofibroblast phenotype associated with disease states such as fibrosis? These studies are expected to have a major impact in the fields of cell biology and wound healing by shifting the study of the regulators of wound healing and source of myofibroblasts to this novel progenitor population. PUBLIC HEALTH RELEVANCE: The knowledge gained from our studies of a novel population of progenitor cells, innate to epithelial tissues, that upon wounding are activated to form the repair cells that modulate the wound response, is expected to reveal novel targets for enhancing wound repair and tissue regeneration. Furthermore, our findings that the progeny of these cells also are a principal source of myofibroblasts, a cell type associated with fibrotic diseases such as PCO and corneal scarring, suggest that the results of our studies also will have a major impact on understanding of mechanisms of disease.